1WCH

Crystal structure of PTPL1 human tyrosine phosphatase mutated in colorectal cancer - evidence for a second phosphotyrosine substrate recognition pocket

Summary for 1WCH

• Entry DOI: 10.2210/pdb1wch/pdb
• Related: 1D5G 1Q7X 3PDZ
• Descriptor: PROTEIN TYROSINE PHOSPHATASE, NON-RECEPTOR TYPE 13, PHOSPHATE ION (3 entities in total)
• Functional Keywords: hydrolase, tyrosine phosphatase, phosphate ion, colorectal cancer alternative splicing, coiled coil, cytoskeleton, polymorphism, structural protein
• Biological source: HOMO SAPIENS (HUMAN)
• Total number of polymer chains: 1
• Total formula weight: 36372.46

Authors

Villa, F.,Deak, M.,Bloomberg, G.B.,Alessi, D.R.,Van Aalten, D.M.F. (deposition date: 2004-11-16, release date: 2004-12-14, Last modification date: 2023-12-13)

Primary citation

Villa, F.,Deak, M.,Bloomberg, G.B.,Alessi, D.R.,Van Aalten, D.M.F.
Crystal Structure of Ptpl1/Fap-1 Human Tyrosine Phosphatase Mutated in Colorectal Cancer: Eveidence for a Second Phosphotyrosine Substrate Recognition Pocket
J.Biol.Chem., 280:8180-, 2005

PubMed Abstract: Protein-tyrosine phosphatase-L1 (PTPL1, also known as FAP-1, PTP1E, PTP-BAS, and PTPN13) is mutated in a significant number of colorectal tumors and may play a role in down-regulating signaling responses mediated by phosphatidylinositol 3-kinase, although the precise substrates are as yet unknown. In this study, we describe a 1.8 A resolution crystal structure of a fully active fragment of PTPL1 encompassing the catalytic domain. PTPL1 adopts the standard PTP fold, albeit with an unusually positioned additional N-terminal helix, and shows an ordered phosphate in the active site. Interestingly, a positively charged pocket is located near the PTPL1 catalytic site, reminiscent of the second phosphotyrosine binding site in PTP1B, which is required to dephosphorylate peptides containing two adjacent phosphotyrosine residues (as occurs for example in the activated insulin receptor). We demonstrate that PTPL1, like PTP1B, interacts with and dephosphorylates a bis-phosphorylated insulin receptor peptide more efficiently than monophosphorylated peptides, indicating that PTPL1 may down-regulate the phosphatidylinositol 3-kinase pathway, by dephosphorylating insulin or growth factor receptors that contain tandem phosphotyrosines. The structure also reveals that four out of five PTPL1 mutations found in colorectal cancers are located on solvent-exposed regions remote from the active site, consistent with these mutants being normally active. In contrast, the fifth mutation, which changes Met-2307 to Thr, is close to the active site cysteine and decreases activity significantly. Our studies provide the first molecular description of the PTPL1 catalytic domain and give new insight into the function of PTPL1.

PubMed: 15611135
DOI: 10.1074/JBC.M412211200

Experimental method

X-RAY DIFFRACTION (1.85 Å)